Substituted triazolo[4,3-c]pyrimidines

ABSTRACT

Substituted triazolo[4,3-c]pyrimidines which are bronchodilators. The pharmacological use of these compounds, and synthetic intermediates for the preparation of these compounds are also described.

TECHNICAL FIELD

The present invention relates to compounds which are known astriazolo[4,3-c]pyrimidines, and more specifically as1,2,4-triazolo[4,3-c]pyrimidines. The pharmacological use of thesecompounds as bronchodilators, pharmaceutical compositions containingthese compounds, and synthetic intermediates for the preparation ofcertain of these compounds are also within the scope of the invention.

BACKGROUND OF THE INVENTION

Some 1,2,4-triazolo[4,3-c]pyrimidines are known to the art. Certain3-amino-1,2,4-triazolo[4,3-c]pyrimidines are disclosed in the patentsdiscussed below:

United Kingdom Pat. No. 859,287 discloses what are believed to be thecompounds 3-amino-7-methyl-5-methylthio-1,2,4-triazolo[4,3-c]pyrimidineand 3-amino-7-chloro-5-methyl-1,2,4-triazolo[4,3-c]pyrimidine.

United Kingdom Pat. No. 873,223 broadly describes6-hydrazinylpyrimidines which may contain alkyl, substituted alkyl,alkenyl, cycloalkyl, alkylthio and halogen sustituents in the 2-, 4- and5-positions. These pyrimidines are used as intermediates in thepreparation of 1,2,4-triazolo[4,3-c]pyrimidines.

United Kingdom Pat. No. 898,408 discloses3-amino-1,2,4-triazolo[4,3-c]pyrimidines which are substituted on thepyrimidine ring at the 5-position by an alkyl, alkylthio, or aminosubstituent, at the 7-position by an alkyl, halogen-substituted alkyl orhalogen substituent, and at the 8-position by hydrogen or an alkyl oralkenyl substituent. This patent also broadly describes, asintermediates, 6-hydrazinylpyrimidines which may contain alkyl,alkylthio or amino in the 2-position, alkyl, substituted alkyl orhalogen in the 4-position, and hydrogen, alkyl or alkenyl in the5-position.

The following related articles diclose the synthesis of certain1,2,4-triazolo[4,3-c]pyrimidines as intermediates in the preparation of1,2,4-triazolo[1,5-c]pyrimidines and as potential branchodilators.

G. W. Miller et al., J. Chem. Soc., 1963, 5642, discloses1,2,4-triazolo[4,3-c]pyrimidines which are substituted at the 3-positionby amino or imino substituents, and on the pyrimidine ring by alkylsubstituents or alkyl and alkenyl substituents.

G. W. Miller et al., J. Chem. Soc., 1963, 3357, discloses the compound3-hydroxy-7-methyl-5-n-propyl-1,2,4-triazolo[4,3-c]pyrimidine.

W. Broadbent et al., J. Chem. Soc., 1963, 3369, discloses the compound3-mercapto-7-methyl-5-n-propyl-1,2,4-triazolo[4,3-c]pyrimidine.

Still other 1,2,4-triazolo[4,3-c]pyrimidines are disclosed in thefollowing articles and patent:

Shiho et al., Yakagaku Zasshi, 1956, 76, 804, discloses1,2,4-triazolo[4,3-c]pyrimidines which are substituted at the 3-positionby alkyl or phenyl substituents, and on the pyrimidine ring by bothmethyl and methoxy substituents.

Temple et al., J. Org. Chem., 1968, 33, 530, discloses the compound8-amino-7-chloro-5-triazolo[4,3-c]pyrimidine-3(2H)-one.

D. J. Brown et al., Aust. J. Chem., 1978, 31, 2505, discloses1,2,4-triazolo[4,3-c]pyrimidines which are substituted at the 3-positionby hydrogen or an alkyl substituent, and on the pyrimidine ring byhydrogen and/or alkyl substituents.

D. J. Brown et al., Aust. J. Chem., 1979, 32, 1585, discloses1,2,4-triazolo[4,3-c]pyrimidines which are substituted at the 3-positionby hydrogen or an alkyl substituent, and on the pyrimidine ring at the5-position by a halogen, hydrazino, methylthio or methyl substituent,and at the 7-position by a methyl substituent. This paper also describesthe compound 6-hydrazinyl-4-methyl-2-methylthiopyrimidine.

U.S. Pat. No. 4,269,980 discloses 5-, 7- and 8-(optionallysubstituted-phenyl)-1,2,4-triazolo[4,3-c]pyrimidines. These compoundsmay be substituted at the 3-position by hydrogen or an alkyl substituentand are anxiolytic agents. This patent also describes, as intermediates,6-hydrazinylpyrimidines which contain an optionally-substituted phenylgroup in the 2, 4 or 5-position.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to 1,2,4-triazolo[4,3-c]pyrimidines whichare bronchodilators. The invention also relates to a method for inducingbronchodilation in a mammal using a 1,2,4-triazolo[4,3-c]pyrimidine ofthe invention, and to pharmaceutical compositions comprising aneffective amount of a 1,2,4-triazolo[4,3-c]pyrimidine of the inventionand a pharmaceutically acceptable carrier. The invention also relates tosynthetic intermediates useful for preparing certain of the1,2,4-triazolo[4,3-c]pyrimidines of the invention.

More specifically, the present invention relates to compounds of theformula I ##STR1## wherein R₃ is hydrogen or lower alkyl; R₅ ishydrogen, lower alkyl, lower alkylthio or benzylthio; R₇ is hydrogen,lower alkyl, halogen, phenyl, N-(lower alkyl)amino, N,N-di(loweralkyl)amino, lower alkylthio or benzylthio; and R₈ is hydrogen, loweralkyl, halogen or phenyl; with the provisos that at least one of R₅ andR₇ is lower alkylthio or benzylthio, or R₇ is N-(lower alkyl)amino orN,N-di(lower alkyl)amino; when R₅ is lower alkylthio, R₇ is halogen,phenyl or lower alkylthio, or R₈ is halogen or phenyl, or R₇ is halogen,phenyl, or lower alkylthio and R₈ is halogen or phenyl; and when R₇ isphenyl, R₅ is benzylthio or lower alkylthio; and pharmaceuticallyacceptable acid-addition salts of the compounds of Formula I.

The present invention also relates to compounds of the Formula II:##STR2## wherein R₁₀ is hydrogen, lower alkyl, lower alkylthio orbenzylthio; R₁₂ is hydrogen, lower alkyl, halogen, phenyl, N-(loweralkyl)amino, N,N-di(lower alkyl)amino, lower alkylthio or benzylthio;and R₁₃ is hydrogen, lower alkyl, halogen or phenyl; with the provisosthat at least one of R₁₀ and R₁₂ is lower alkylthio or benzylthio, orR₁₂ is N-(lower alkyl)amino or N,N-di(lower alkyl)amino; when R₁₀ islower alkylthio, R₁₂ is lower alkylthio or phenyl, or R₁₃ is chloro,fluoro or phenyl, or R₁₂ is lower alkylthio or phenyl and R₁₃ is chloro,fluoro or phenyl; and when R₁₂ is phenyl, R₁₀ is benzylthio or loweralkylthio.

"Lower alkyl" as used in the instant specification and claims designatesstraight or branched-chain alkyl groups containing one to four carbonatoms. Preferred lower alkyl groups are methyl, ethyl and n-propyl.

"Halogen" as used in the instant specification and claims designatesfluoro, chloro and bromo.

Presently preferred compounds of Formula I are those wherein R₅ isalkylthio and R₇ or R₈ is halogen. Another preferred subclass ofcompounds is that wherein R₇ is N-lower alkylamino or N,N-di(loweralkyl)amino.

Presently preferred compounds of Formula II are those wherein R₁₀ ishydrogen, lower alkyl or benzylthio; R₂ is lower alkyl, phenyl, N-(loweralkyl)amino, N,N-di(lower alkyl)amino or lower alkylthio; and R₁₃ ishydrogen, lower alkyl, halogen or phenyl. Another preferred subclass ofcompounds of Formula II is that wherein R₁₀ is lower alkylthio and R₁₂is phenyl. Still another preferred subclass of compounds are thosewherein R₁₀ and R₁₂ are lower alkylthio and R₁₃ is hydrogen.

Specific examples of preferred compounds of Formula I which are activeat concentrations of 10 μg per ml or lower in protecting againsthistamine-induced contraction of isolated guinea pig tracheal tissueare: 5-methylthio-7-chloro-1,2,4-triazolo[4,3-c]pyrimidine;8-chloro-3-ethyl-5-methylthio-1,2,4-triazolo[4,3-c]pyrimidine; and3-ethyl-8-fluoro-5-methylthio-1,2,4-triazolo[4,3-c]pyrimidine. Thisassay is discussed in greater detail below.

The bronchodilator activity of the compounds of Formula I was assessedby the measurement of effects on isolated tracheal spirals. This is awell-known and long established in vitro test method. The bronchodilatoractivity was determined as follows: Female guinea pigs were sacrificed,and each trachea removed and cut into a spiral strip. This strip wasmounted in a constant temperature (37° C.) muscle bath having a volumeof approximately 15 ml. The bathing medium was Krebs-Henseleit solution.Movement of the tracheal strip was measured by means of an isometrictransducer connected to an electric recorder. The bath was aerated witha mixture of 95% carbon dioxide and 5% oxygen. Contractions were inducedin the strips by the addition of a suitable amount of histamine,acetylcholine or barium chloride. The amount of a given compound ofFormula I (measured in μg/ml) required to provide greater than 75%relaxation of drug-induced contraction is considered an effectiveconcentration. For comparison, a well known standard bronchodilator,aminophylline, requires concentrations of 50 μg/ml versus histamine, 100ug/ml versus acetylcholine and 10 μ/ml versus barium chloride to providegreater than 75% relaxation.

Some of the compounds of Formula I were also found to have activity asmucolytics in an in vitro test for mucus production in which rats areorally dosed with compound prior to sacrifice, and the trachea isisolated and incubated with radiolabelled glucosamine. The effect ofcompounds of Formula I on the incorporation of glucosamine intoextracellular mucus is determined. An active compound reducesincorporation of glucosamine.

The compounds of Formula I may be administered to mammals in order toobtain bronchodilation. The compounds may be administered orally,parenterally or by inhalation. Preferably, the compounds areadministered parenterally. The usual effective human dose will be 0.1 to50 mg/kg of body weight.

Acid-addition salts of compounds of Formula I are generally prepared byreaction of a compound of Formula I with an equimolar amount of arelatively strong acid, preferably an inorganic acid such ashydrochloric, sulfuric or phosphoric acid, in a polar solvent. Isolationof the salt is facilitated by the addition of a solvent in which thesalt is insoluble, an example of such a solvent being diethyl ether.

The compounds of Formula I wherein R₃, R₅, R₇ and R₈ as defined abovemay be prepared via the following Reaction Scheme I wherein each "Alk"is independently lower alkyl. ##STR3##

In Reaction Scheme I, a compound of Formula III is reacted with anorthoester of Formula IIIA to provide a compound of Formula I.Orthoesters of Formula IIIA are well known and readily available.Examples of suitable orthoesters of Formula IIIA include trimethylorthoformate, triethyl orthoformate, triethyl orthoacetate, triethylorthopropionate trimethyl orthobutyrate, trimethyl orthoisobutyrate andthe like. Since the orthoesters of Formula IIIA are liquids, it isconvenient to mix the intermediates of Formula III with an excess oforthoester and heat the mixture at reflux until reaction is complete.Good yields of the desired compounds of Formula I are isolated byconventional methods. When R₅ is hydrogen, it is necessary to monitorthe reaction as it proceeds, or rearrangement to the 1,5-c isomer mayoccur. Monitoring is conducted by conventional methods such asthin-layer chromatography or nuclear magnetic resonance analysis. Thereaction is readily halted by cooling. The structural assignments aremade based on infrared and nuclear magnetic spectral analyses. Theproducts are generally white crystalline solids.

In many cases, the intermediates of Formula III are novel compounds, thenovel intermediates being those of the more specific Formula II above.

The compounds of Formula III wherein R₃, R₅ and R₈ are as defined aboveand R₇ is hydrogen, lower alkyl, halogen, phenyl, lower alkylthio orbenzylthio may be prepared as follows in Reaction Scheme II. ##STR4##

In Reaction Scheme II, a substituted 4-chloropyrimidine of Formula IV isreacted with hydrazine hydrate to provide an intermediate of Formula Vwhich may then be reacted via Reaction Scheme I to provide certaincompounds of Formula I. Compounds of Formula IV are known or may beprepared from known starting materials using conventional methods. Thereaction of Reaction Scheme II is generally carried out by adding twoequivalents of hydrazine hydrate to a solution of the compound ofFormula IV. The solvent employed is generally a lower alkanol. Thereaction is facile and is generally carried out at moderatetemperatures, for example, from -20° C. to the reflux temperature of thereaction solvent. The solid product is separated by conventional methodssuch as filtration, extraction or chromotography, and then is availablefor use in Reaction Scheme I.

The compounds of Formula III wherein R₃, R₅ and R₈ are as defined aboveand R₇ is N-(lower alkyl)amino or N,N-di(lower alkyl)amino may beprepared as follows in Reaction Scheme III wherein "Alk" is lower alkyland R₁₅ is hydrogen or lower alkyl. ##STR5##

In Reaction Scheme III, a 4-chloro-6-pyrimidine of Formula VI is reactedwith a primary or secondary lower alkyl amine of Formula VIA to providean intermediate of Formula VII. Compounds of Formula VI are known or maybe prepared from known starting materials using conventional methods.Generally, the compound of Formula VI and amine of Formula VIA areheated together in the absence of solvent, or optionally (andpreferably) in the presence of a solvent which does not participate inthe reaction such as water. Two equivalents of the amine are preferablyused. Alternatively, one equivalent of the amine may be replaced by aninorganic base to neutralize the hydrogen chloride, but lower yields aregenerally obtained. The reaction mixture is heated at a temperature upto or at the reflux temperature. A temperature is chosen which providesan adequate reaction rate. Good yields of the desired products areisolated by conventional methods such as filtration, extraction orchromatography. The novel intermediates of Formula VII are solids whosestructural assignments are confirmed by infrared and nuclear magneticresonance spectral analyses. The intermediates of Formula III may thenbe employed in Reaction Scheme I to prepare certain compounds of FormulaI.

The compounds of Formula III wherein R₃, R₅ and R₇ are as defined aboveand R₇ is lower alkylthio may be prepared as follows in Reaction SchemeIV wherein "Alk" is lower alkyl and "M" is an alkali metal. ##STR6##

In Reaction Scheme IV, a 6-chloro-4-hydrazinopyrimidine of Formula VIIIis reacted with an alkali metal alkylthiolate of Formula VIIIA toprovide a 6-(alkylthio)pyrimidylhydrazine of Formula IX. Compounds ofFormula VIII are known or may be prepared from known starting materialsusing conventional methods. The reaction of Reaction Scheme IV isgenerally carried out in a suitable solvent such as an alcohol. Suitablealkali metal alkylthiolates include sodium methyl mercaptide, potassiummethyl mercaptide, sodium ethyl mercaptide and the like. The reaction isgenerally promoted by heating the mixture, for example, at the refluxtemperature of the reaction mixture.

The following examples are provided to illustrate the methods used inthe invention. They are not intended to limit the invention.

EXAMPLE 1 Preparation of7-Chloro-5-methylthio-1,2,4-triazolo[4,3-c]pyrimidine

A mixture of 7.0 g (0.037 mole) of4-chloro-6-hydrazino-2-methylthiopyrimidine and 100 ml of triethylorthoformate was heated at reflux for 48 hours. Cooling provided aprecipitate which was isolated by filtration, and then recrystallizedfrom an ethanol-heptane mixture, with treatment with decolorizingcharcoal. The product was red crystals of7-chloro-5-methylthio-1,2,4-triazolo[4,3-c]pyrimidine, m.p. 164°-165° C.

Analysis: Calculated for C₆ H₅ N₄ ClS: %C, 35.9; %H, 2.5; %N, 27.9;Found: %C, 36.0; %H, 2.5; %N, 28.5.

EXAMPLES 2-18

Using the method of Example 1, and starting with the indicatedpyrimidine of Formula III, the indicated compounds of Formula I wereprepared (Table I). The structures were confirmed by elemental, infraredand nuclear magnetic resonance spectral analyses.

                                      TABLE I                                     __________________________________________________________________________                              Product of Formula I                                Ex.                       (m.p. in °C.);                               No.                                                                              Pyrimidine of Formula III                                                                    Orthoester                                                                            Recrystallization Solvent                           __________________________________________________________________________    2  2-benzylthio-4-hydrazino-6-                                                                  triethyl                                                                              5-benzylthio-3-ethyl-7-n-propyl-                       n-propylpyrimidine                                                                           orthopropionate                                                                       1,2,4-triazolo[4,3-c]pyrimidine                                               (70-72); hexanes                                    3  2-benzylthio-4-hydrazino-6-                                                                  triethyl                                                                              5-benzylthio-7-n-propyl-1,2,4-                         n-propylpyrimidine                                                                           orthoformate                                                                          triazolo[4,3-c]pyrimidine                                                     (74-75); hexanes                                    4  2-benzylthio-4-hydrazino-6-                                                                  triethyl                                                                              5-benzylthio-3-methyl-7-n-                             n-propylpyrimidine                                                                           orthoacetate                                                                          propyl-1,2,4-triazolo[4,3-c]-                                                 pyrimidine (137-139); cyclohexane                   5  6-(N,N--diethylamino)-4-                                                                     trimethyl                                                                             7-(N,N--diethylamino)-5-methyl-                        hydrazino-2-methyl-                                                                          orthoformate                                                                          1,2,4-triazolo[4,3-c]pyrimidine                        pyrimidine             (133-135); benzene/hexanes                          6  5-bromo-4-hydrazino-2-                                                                       triethyl                                                                              8-bromo-3-ethyl-5-methylthio-                          methylthiopyrimidine                                                                         orthopropionate                                                                       1,2,4-triazolo[4,3-c]pyrimidine                                               (162-165); benzene/hexanes                          7  5-bromo-4-hydrazino-2-                                                                       triethyl                                                                              8-bromo-3-methyl-5-methylthio-                         methylthiopyrimidine                                                                         orthoacetate                                                                          1,2,4-triazolo[4,3-c]pyrimidine                                               (220-222); ethanol                                  8  5-bromo-4-hydrazino-2-                                                                       triethyl                                                                              8-bromo-5-methylthio-1,2,4-                            methylthiopyrimidine                                                                         orthoformate                                                                          triazolo[4,3-c]pyrimidine                                                     (166-168); ethyl acetate/hexanes                    9  5-chloro-4-hydrazine-2-                                                                      triethyl                                                                              8-chloro-3-ethyl-5-methylthio-                         methylthiopyrimidine                                                                         orthopropionate                                                                       1,2,4-triazolo[4,3-c]pyrimidine                                               (167-169); ethyl acetate                            10 2,6-bis(methylthio)-4-                                                                       triethyl                                                                              5,7-bis(methylthio)-1,2,4-                             hydrazinopyrimidine                                                                          orthoformate                                                                          triazolo[4,3-c]pyrimidine (179-181);                                          ethanol/hexanes                                     11 6-chloro-4-hydrazino-2-                                                                      triethyl                                                                              7-chloro-5-methylthio-8-phenyl-                        methylthio-5-phenylpyrimidine                                                                orthoformate                                                                          1,2,4-triazolo[4,3-c]  pyrimidine                                             (170-171); benzene/hexanes                          12 6-chloro-4-hydrazino-2-                                                                      triethyl                                                                              7-chloro-3-methyl-5-methylthio-                        methylthio-5-phenylpyrimidine                                                                orthoacetate                                                                          8-phenyl-1,2,4-triazolo[4,3-c]-                                               pyrimidine (169-172); cyclohexane                   13 6-chloro-4-hydrazino-2-                                                                      triethyl                                                                              7-chloro-3-ethyl-5-methylthio-                         methylthio-5-phenylpyrimidine                                                                orthopropionate                                                                       8-phenyl-1,2,4-triazolo[4,3-c]-                                               pyrimidine (156-158); benzene/hexanes               14 5-fluoro-4-hydrazino-2-                                                                      triethyl                                                                              8-fluoro-3-methyl-5-methyl-                            methylthiopyrimidine                                                                         orthoacetate                                                                          thio-1,2,4-triazolo[4,3-c]-                                                   pyrimidine (234-236); ethanol                       15 5-fluoro-4-hydrazino-2-                                                                      triethyl                                                                              8-fluoro-3-ethyl-5-methylthio-                         methylthiopyrimidine                                                                         orthopropionate                                                                       1,2,4-triazolo[4,3-c]pyrimidine                                               (139-141); benzene/hexanes                          16 5-fluoro-4-hydrazino-2-                                                                      triethyl                                                                              8-fluoro-5-methylthio-1,2,4-                           methylthiopyrimidine                                                                         orthoformate                                                                          triazolo[4,3-c]pyrimidine (140-142);                                          none                                                17 5-chloro-4-hydrazino-2-                                                                      triethyl                                                                              8-chloro-3-methyl-5-methylthio-                        methylthiopyrimidine                                                                         orthoacetate                                                                          1,2,4-triazolo[4,3-c]pyrimidine                                               (228-229); glyme/hexanes                            18 5-chloro-4-hydrazino-2-                                                                      triethyl                                                                              8-chloro-5-methylthio-1,2,4-                           methylthiopyrimidine                                                                         orthoformate                                                                          triazolo[4,3-c]pyrimidine (155-157);                                          ethanol/hexanes                                     __________________________________________________________________________

EXAMPLE 19 Preparation of5-Ethylthio-7-phenyl-1,2,4-triazolo[4,3-c]pyrimidine

A mixture of 5.0 g (0.020 mole) of2-ethylthio-4-hydrazino-6-phenylpyrimidine and 50 ml of triethylorthoformate was heated at its reflux temperature for about 65 hours,and was then allowed to cool to about 20° C. The mixture was poured intoice, and the precipitated product was collected by filtration, andwashed with hexanes and air dried. Recrystallization from a 50/50mixture of cyclohexane and ethyl acetate provided yellowish crystals of5-ethylthio-7-phenyl-1,2,4-triazolo[4,3-c]pyrimidine, m.p. 168°-170° C.

Analysis: Calculated for C₁₃ H₁₂ N₄ S: %C, 60.9; %H, 4.7; %N, 21.9;Found: %C, 61.1; %H, 4.6; %N, 22.3.

To a solution of 3.6 g of5-ethylthio-7-phenyl-1,2,4-triazolo[4,3-c]pyrimidine in 100 ml of hotethanol was added 1.4 g of concentrated sulfuric acid. The mixture wascooled, an equal volume of diethyl ether was added and the precipitatewas collected by filtration. The precipitate was recrystallized from amixture of methanol and diethyl ether to provide5-ethylthio-7-phenyl-1,2,4-triazolo[4,3-c]pyrimidine dihydrogen sulfatehydrate, m.p. 213°-214° C.

Analysis: Calculated for C₁₃ H₁₂ N₄ S.H₂ SO₄.2/3 Hhd 2O: %C, 50.4; %H,4.1; %N, 13.1; Found: %C, 50.4; %H, 4.4; %N, 13.1.

EXAMPLE 20 Preparation of5-Ethylthio-3-methyl-7-phenyl-1,2,4-triazolo[4,3-c]pyrimidine

Using the method of Example 19,2-ethylthio-4-hydrazino-6-phenylpyrimidine was reacted with triethylorthoacetate to provide5-ethylthio-3-methyl-7-phenyl-1,2,4-triazolo[4,3-c]pyrimidine which wasrecrystallized from a 50/50 mixture of ethyl acetate/cyclohexanes toprovide white crystals of5-ethylthio-3-methyl-7-phenyl-1,2,4-triazolo[4,3-c]pyrimidine, m.p.219.5°-220° C.

Analysis: Calculated for C₁₄ H₁₄ N₄ S: %C, 62.2; %H, 5.2; %N, 20.7;Found: %C, 62.2; %H, 5.1; %N, 21.1.

Using the method of Example 19, the above free base was converted to therecrystallized dihydrogen sulfate salt, m.p. 210°-212° C.

Analysis: Calculated for C₁₄ H₁₄ N_(4S).H₂ SO_(4:) %C, 45.6; %H, 4.4;%N, 15.2; Found: %C, 45.5; %H, 4.4; %N, 15.4.

EXAMPLE 21 Preparation of5-Benzylthio-7-phenyl-1,2,4-triazolo[4,3-c]pyrimidine

Using the method of Example 19,2-benzylthio-4-hydrazino-6-phenylpyrimidine was reacted with triethylorthoformate, and the reaction product was isolated as the dihydrogensulfate salt. Recrystallization from a methanol/diethyl ether mixtureprovided 5-benzylthio-7-phenyl-1,2,4-triazolo[4,3-c]pyrimidinedihydrogen sulfate hydrate, m.p. 183°-185° C.

Calculated for C₁₈ H₁₄ N₄ S.H₂ SO₄.2/3 H₂ O: %C, 50.4; %H, 4.1; %N,13.1; Found: %C, 50.3; %H, 4.4; %N, 13.1.

EXAMPLE 22 Preparation of5-Benzylthio-3-methyl-7-phenyl-1,2,4-triazolo[4,3-c]pyrimidine

Using the method of Example 19,2-benzylthio-4-hydrazino-6-phenylpyrimidine was reacted with triethylorthoacetate, and the reaction product was isolated as the dihydrogensulfate salt. Recrystallization from a methanol/diethyl ether mixtureprovided 5-benzylthio-3-methyl-7-phenyl-1,2,4-triazolo[4,3-c]pyrimidinedihydrogen sulfate hydrate, m.p. 195°-196° C.

Analysis: Calculated for C₁₉ H₁₆ N₄ S.H₂ SO₄.1/2 H₂ O: %C, 51.9; %H,4.3; %N, 12.7; Found: %C, 51.6; %H, 4.3; %N, 13.0.

EXAMPLE 23 Preparation of5-Benzylthio-3-ethyl-7-phenyl-1,2,4-triazolo[4,3-c]pyrimidine

Using the method of Example 19,2-benzylthio-4-hydrazino-6-phenylpyrimidine was reacted with triethylorthopropionate, and the reaction product was isolated as5-benzylthio-3-ethyl-7-phenyl-1,2,4-triazolo[4,3-c]pyrimidine dihydrogensulfate, m.p. 184°-185° C.

Analysis: Calculated for Chd 20H₁₈ N₄ S: %C, 54.0; %H, 4.5; %N, 12.6;Found: %C, 54.1; %H, 4.7; %N, 12.7.

EXAMPLE 24 Preparation of3,5-Dimethyl-7-methylthio-1,2,4-triazolo[4,3-c]pyrimidine

A mixture of 2.5 g (0.015 mole) of4-hydrazino-2-methyl-6-methylthiopyrimidine and 50 ml of triethylorthoacetate was heated at its reflux temperature for five days, and wasthen cooled. The solid was separated by filtration and recrystallizedwith treatment with decolorizing charcoal from first an ethylacetate-hexane mixture, and then a benzene-hexane mixture to provide3,5-dimethyl-7-methylthio-1,2,4-triazolo[4,3-c]pyrimidine, m.p.201°-203° C.

Calculated for C₈ H₁₀ N₄ S: %C, 49.5; %H, 5.2; %N, 28.8; Found: %C,49.6; %H, 5.2; %N, 28.9.

EXAMPLES 25-26

Using the method of Example 24 and starting with the indicatedpyrimidines of Formula III, the following compounds of Formula I wereprepared (Table II).

                                      TABLE II                                    __________________________________________________________________________    Ex.                     Product of Formula I                                  No.                                                                              Pyrimidine of Formula III                                                                  Orthoester                                                                            (m.p. in °C.)                                  __________________________________________________________________________    25 4-hydrazino-2-methyl-6-                                                                    triethyl                                                                              5-methyl-7-methylthio-1,2,4-                             methylthiopyrimidine                                                                       orthoformate                                                                          triazolo[4,3-c]pyrimidine (202-204)                   26 4-hydrazino-2-methyl-6-                                                                    triethyl                                                                              3-ethyl-5-methyl-7-methylthio-1,2,4-                     methylthiopyrimidine                                                                       orthopropionate                                                                       triazolo[4,3-c]pyrimidine (190-192)                   __________________________________________________________________________

EXAMPLE 27

To a cold (ice bath) stirred solution of 25 g (0.09 mole) of4,6-dichloro-2-methylthio-5-phenylpyrimidine in 250 ml of methanol wasadded slowly 10 g (0.2 mole) of hydrazine hydrate. After one hour themixture was allowed to warm to about 20° C., and was then stirred at 20°C. for about 16 hours. The precipitate was separated by filtration toprovide 4-chloro-6-hydrazino-2-methylthio-5-phenylpyrimidine.Recrystallization twice from hexanes/cyclohexane provided whitecrystals, m.p. 134°-135° C.

Analysis: Calculated for C₁₁ H₁₁ ClN₄ S: %C, 49.5; %H, 4.15; %N, 21.0;Found: %C, 49.4; %H, 4.0; %N, 20.9.

EXAMPLES 28-31

Using the method of Example 27 and starting with the indicated4-chloropyrimidine, the following intermediates of Formula III wereprepared (Table III).

                  TABLE III                                                       ______________________________________                                        Ex.  4-Chloropyrimidine                                                                           Intermediate of                                           No.  Intermediate   Formula III (m.p. in °C.)                          ______________________________________                                        28   4-chloro-5-fluoro-2-                                                                         5-fluoro-4-hydrazino-2-methylthio-                             methylthiopyrimidine                                                                         pyrimidine (not taken)                                    29   4,5-dichloro-2-                                                                              5-chloro-4-hydrazino-2-methylthio-                             methylthiopyrimidine                                                                         pyrimidine (not taken)                                    30   2-benzylthio-4-chloro-                                                                       2-benzylthio-4-hydrazino-6-phenyl-                             6-phenylpyrimidine                                                                           pyrimidine (140-142)                                      31   4-chloro-2-ethylthio-6-                                                                      2-ethylthio-4-hydrazino-6-phenyl-                              phenylpyrimidine                                                                             pyrimidine (110-112)                                      ______________________________________                                    

EXAMPLE 32

A mixture of 41 g (0.28 mole) of 4-chloro-6-hydrazinopyrimidine and 90 g(0.3 mole) of sodium methylthiolate in 500 ml of methanol was heated atits reflux temperature for 15 hours. The mixture was then cooled toabout 20° C., and the resulting solid was separated by filtration andthe filtrate evaporated. The residue and the precipitate were combinedand stirred in 500 ml of water. The product was separated by filtration,washed with more water and dried. The product was4-hydrazino-6-methylthiopyrimidine, m.p. 156°-159° C. The structuralassignment was confirmed by nuclear magnetic resonance and infraredspectral analyses.

EXAMPLES 33-34

Using the method of Example 32, the following intermediates of FormulaIII were prepared from the indicated known4-chloro-6-hydrazinopyrimidines (Table IV).

                  TABLE IV                                                        ______________________________________                                        Ex.  4-Choro-6-     Intermediate of                                           No.  hydrazinopyrimidine                                                                          Formula III (m.p. in °C.)                          ______________________________________                                        33   4-chloro-6-hydrazino-                                                                        2,4-bis(methylthio)-6-hydrazino-                               2-methylthiopyrimidine                                                                       pyrimidine (120-125)                                      34   4-chloro-6-hydrazino-                                                                        4-hydrazino-2-methyl-6-methylthio-                             2-methylpyrimidine                                                                           pyrimidine (155-157)                                      ______________________________________                                    

EXAMPLE 35

To a suspension of 3.00 g (18.9 mmole) of4-chloro-6-hydrazino-2-methylpyrimidine in 50 ml of water was added 3.00g (41.2 mmole) of N,N-diethylamine, and the resulting mixture was thenheated at reflux for about 20 hours. The mixture was basified with tenpercent aqueous sodium hydroxide solution and extracted with five 40 mlportions of chloroform. The combined extracts were washed with three 50ml portions of saturated sodium chloride solution, and were then driedover magnesium sulfate and evaporated. The residue was triturated withdiethyl ether and cooled. The precipitate was separated by filtrationand recrystallized with treatment with decolorizing charcoal from abenzene/hexanes (6/15) mixture to provide an off-white solid which waschiefly 4-(N,N-diethylamino)-6-hydrazino-2-methylpyrimidine, m.p.95°-103° C. Nuclear magnetic resonance spectral analysis showed about15% starting material present.

EXAMPLE 36 Preparation of 2-Benzylthio-4-hydrazino-6-n-propylpyrimidinePart A: Preparation of 2-Benzylthio-4-hydroxy-6-n-propylpyrimidine

A mixture of 51.1 g (0.3 mole) of4-hydroxy-6-n-propylpyrimidine-2-thiol, 51.3 g (0.3 mole) of benzylbromide, 100 ml of dioxane and 500 ml of 1N aqueous sodium hydroxidesolution was heated at 80° C. for four hours. After cooling, the solidwas collected by filtration to provide white crystals of2-benzylthio-4-hydroxy-6-n-propylpyrimidine, m.p. 122°-126° C.

Part B: Preparation of 2-Benzylthio-4-chloro-6-n-propylpyrimidine

A mixture of 72 g (0.28 mole) of2-benzylthio-4-hydroxy-6-n-propylpyrimidine (from Part A) and 100 ml ofphosphorus oxychloride was heated at reflux for three hours, and wasthen allowed to cool to 20° C. After evaporating in vacuo the residuewas poured into ice water with vigorous stirring. The mixture wasextracted with three 75 ml portions of diethyl ether, and the extractswere dried over magnesium sulfate and evaporated to provide a yellow oilresidue of 2-benzylthio-4-chloro-6-n-propylpyrimidine.

Part C: Preparation of 2-Benzylthio-4-hydrazino-6-n-propylpyrimidine

A mixture of 40 g (0.014 mole) of2-benzylthio-4-chloro-6-n-propylpyrimidine (from Part B) and 15 g (0.3mole) of hydrazine hydrate in 300 ml of ethanol was heated at reflux for2 hours, cooled and evaporated. Water was added to the residue. Thewhite solid was collected by filtration and dried to provide2-benzylthio-4-hydrazino-6-n-propylpyrimidine. The structural assignmentwas confirmed by infrared and nuclear magnetic resonance spectralanalyses.

What is claimed is:
 1. A compound of the formula ##STR7## wherein R₃ or lower alkyl; R₅ is hydrogen, lower alkyl, lower alkylthio or benzylthio; R₇ is hydrogen, lower alkyl, halogen, phenyl, N-(lower alkyl)amino, N,N-di(lower alkyl)amino, lower alkylthio or benzylthio; and R₈ is hydrogen, lower alkyl, halogen or phenyl; with the provisos that at least one of R₅ and R₇ is lower alkylthio or benzylthio, or R₇ is N-(lower alkyl)amino or N,N-di(lower alkyl)amino; when R₅ is lower alkylthio, R₇ is halogen, phenyl or lower alkylthio, or R₈ is halogen or phenyl, or R₇ is halogen, phenyl or lower alkylthio and R₈ is halogen or phenyl; and when R₇ is phenyl, R₅ is benzylthio or lower alkylthio; or a pharmaceutically acceptable acid-addition salt thereof.
 2. A compound according to claim 1, wherein R₅ is alkylthio and R₇ or R₈ is halogen.
 3. A compound according to claim 1, wherein R₇ is N-lower alkylamino or N,N-di(lower alkyl)amino.
 4. A bronchodilator pharmaceutical composition comprising an effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier.
 5. A method for obtaining bronchodilation in a mammal, comprising administering an effective amount of a compound according to claim 1 to said mammal.
 6. A method according to claim 5 wherein said compound is administered parenterally. 